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Insulin resistance (IR) is a critical driver of later cardiometabolic alterations. A comprehensive understanding of the molecular mechanisms underlying the initial development of childhood IR is essential for timely prevention and intervention. In this study, we aimed to assess the association between IR and blood DNA methylation in a longitudinal study from childhood into adolescence. Methods The PUBMEP study included a longitudinal core of 90 children with paired blood samples collected at both pre-pubertal and pubertal stages. For cross-sectional analyses, this sample was expanded to 99 pre-pubertal and 129 pubertal participants. IR status was defined according to clinically relevant sex- and pubertal stage specific HOMA-IR cut-offs, as recommended by pediatric expert clinicians. Genotype data was obtained with the Infinium Global Screening Array, and blood DNA methylation sites with the Infinium MethylationEPIC BeadChip. Epigenome-wide associations with IR status and trajectories were tested using linear models in the longitudinal and cross-sectional sets. FDR-adjusted significant CpG sites were assessed with sex- and age-standardised cardiometabolic z-scores (adiposity, lipids, blood pressure, glycaemia and IR) at each stage. mQTL analyses were performed to identify genetic variants that drive IR-associated methylation signals. Results We identified 120 CpG sites related to obesity-associated IR in the context of pubertal transition that remained significant after global FDR correction (FDR < 0.05). These CpG sites showed distinct methylation profiles that tracked IR trajectories from prepuberty to puberty, with consistent differences across children whose IR improved, worsened or remained stable, with several of them also related to cardiometabolic traits at pubertal stage, including adiposity measures, blood pressure and glycaemic indices. Among the FDR-significant CpG sites with biological relevance for IR, methylation at CpG sites annotated to SLC2A9, PEPD, TSC2, EGLN3, EHD2 and VASN showed consistent associations with pubertal HOMA-IR z-score and, for several loci, with adiposity and blood pressure measures, with methylation changes paralleling IR worsening, improvement or stability across puberty. An mQTL look-up in GoDMC identified 25 cis SNP CpG associations corresponding to 20 of the 120 CpG sites, including CpG sites in SLC2A9 and TSC2, indicating that only a fraction of these IR-associated CpG sites is likely to be partly influenced by nearby genetic variants. Conclusion This longitudinal EWAS in children with obesity shows that specific blood DNA methylation signatures mirror IR status and track its evolution across the pubertal transition, with opposing methylation trajectories distinguishing improving from persistent IR. The identification of CpG sites at VASN, SLC2A9, PEPD, EGLN3, EHD2 and TSC2 links IR trajectories to pathways involved in vascular signalling, urate transport, extracellular matrix remodelling, and hypoxia sensing and nutrient signalling. Complementary mQTL analyses suggest that while some of this epigenetic variation is influenced by local genetic factors, a substantial component is likely acquired in response to metabolic and external exposures. If replicated and functionally characterised, these findings may help refine our understanding of the early molecular architecture of obesity-related IR and inform future strategies for cardiometabolic risk assessment and timing of preventive interventions."],"publicationDate":"2026-02-24","publisher":"Springer Science and Business Media LLC","embargoEndDate":null,"sources":["Crossref","Cardiovasc Diabetol"],"formats":["application/pdf"],"contributors":null,"coverages":null,"bestAccessRight":{"code":"c_abf2","label":"OPEN","scheme":"http://vocabularies.coar-repositories.org/documentation/access_rights/"},"container":{"name":"Cardiovascular 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